Carboxylic acid amides of the cyclopentanopolyhydrophenanthrene series



Patented Feb. 20, 1940 UNITED STATES PATENT OFFICE CARBOXYLIC ACID AIWIDES OF THE CYCLOPEN TAN OPOLYHYDROPHENAN f THRENE, SERIES Karl Miescher, Riehen, and Albert Wettstein,

Basel, Switzerland, assignors to the firm o1 Society of Chemical Industry in Baslc, Basel,

Switzerland No Drawing; Application November 18, @1938,

Serial No. 241,276. In Switzerland March 17,

- This invention relates to the manufacture of cyclopentanopolyhydrophenanthrene carboxylic acid amidesor the free acids by treating a free or esterified .a-hydroxynitrile of the cyclopen 5 tanopolyhydrophenanthrene series with an acid and if desired subsequently with an alkaline.

agent.' Y

Suitable parent materials are obtained, for example, by the action of hydrogen cyanide on a: carbonyl compound containingthe steroid skele ton. In carrying out this condensation it is often an advantage that there should be present .a small proportionof a substance of basic action, for instance an alkali hydroxide or an alkaline.

" earth hydroxide or a carbonate or bicarbonate of either of these, an alkalisalt of a feeble orgarlic acid, for instance an alkali cyanide, an

organic base or the like. -The cyanohydrine thus 20 obtained '(see S. Kuwada '& Miyasaka', Journ. may be converted before the treatment oflthe present invention into the more stable and there-.- fore more easily purified esters bythe action 'of an esterifying agent; for instance, they may be a-halogen-compounds. The parent material may, be derived from any .compound of the cyclopentanopolyhydrophenanthrene series, for example from androstane, pregnane, oestrane, their stereobe for the rest saturatedor monoor poly-unsaturated. The nitrile group or groups may beunited' directly to the nuclear skeleton or may be separated therefrom by one or more carbon atoms;

the free or esterified hydroxyl groups in cc-POSition are of tertiaryor secondary nature.

The process comprises treating the parent ma-, terial in substance, in solution orin suspension.

with an'acid agent, for. instance a mineral acid, 40 such as a'hydrogen halide, sulfuric acid or-phosphoric acid or an acid salt, an inorganic acid anhydride, a. strong organic acid, for instance formic acidorthe like. Suitable solvents or diluents are for example alcohols, ethers, chlorinated hydro-' carbons, for instance chloroform, ethylene chlo'-' ride or chlorobenzene; also acetic acid, hydro-- carbons or the like. The most favourable'condb' eliminated in the form of acid or water or (in .00

case the process is conducted under reducing pharmac. Soc. Japan, vol. 57, page 96 (1937) converted into the'u-acyloxy compounds or'thef isomerides, derivatives and homologues, and may 4 Claims. (c1. 26039'l).

conditions, for instance in'thepresence of hydrogen iodide and phosphorus) exchanged for hydrogen.

The products obtained byv the action of acid agents may finally be treated in the crude form,

or after they have been separated and purified, with an alkaline agent. For this purpose the hydroxide of an alkali-metal or alkaline earth metal or a carbonate of either metal in absolute or aqueous alcohol ora metal alcoholate or the like may be used. In this manner by a comparatively gentle action parent material which has not been changed may be split into its fundamental carbonyl compounds and these may be removed for example by taking advantage of their greatersolubility or by means of carbonyl reagents and further used in synthesis. Quite generally in this manner ester groups, especially secondary ester groups,,may easily be saponified,

whereas the saponification or eliminationv otter tiary ester groups (accompanied by reformation of free .hydroxyl or formation of a new double linking) generally requires somewhat more energetic conditions. Energetic action mayserve especiallyfor finally converting acid amide groups which may be present into carboxylic acids.

Both the treatment with acid and that with alkaline agent may be conducted in stages, the several stages being conducted under the same or varied conditions, for example u-acetoxycarboxylic acid amides obtained from a-acetoxynitriles by means of an'acid agent mayeasily be separated from by-products by the gentle action of an alkaline agent; by energetic alkaline saponification they may heconverted into oc-hYdIQXJCfiI- boxylicacid amides and finally under strongly alkaline conditions of reaction the latter become a-hydroxycarboxylic acids. By the action of powerful acid "agents for eliminating water there may bev obtained from the corresponding .a-hydroxycarboxylic. acid amides unsaturated amides (and finallyby means of alkalis unsaturated acids) or under. reducing, acid conditions a-desoxycarboxyli'c acids.

."By the invention therefore there may be obtained u-acyl0xy-, a-hydroxy-, a-halogen, ocdesoxyor cap-unsaturated carboxylic acids of the cyclopentanopolyhydrophenanthrene series or their amides. These substances are Very important intermediate products in the manufac-' vture of therapeutically valuable compounds,

especially having reactivity of corpus luteum hormone or of the hormone of the suprarenal capsule cortex. v a

The following examples illustrate the invention, the parts being by weight:v

' Example 1 1 part of t-dehydro-androstero ne-cyanohydrindiacetate of melting point 215 to 21. 7 C. is dissolved in 3 parts of chloroform and after addi tion of 3 parts of alcoholic hydrochloric acid solution of 50 per cent. strength the mixture is kept in a closed vessel at room temperature for 2 days, whereby crystallisation occurs. poured into water, chloroform is removed at a low temperature in a vacuum and the crude product thus obtained is filtered with suction. It is finally heated under reflux for 2 hours with a solution of 0.7 part of potassium hydroxide in 50 parts of methanol and the alkaline solution is then poured into water. The flocks thus precipitated are filtered with suction, washed with normal alkali lye and then with water, sharply dried and then extracted twice, each time with 50 parts of boiling hexane. By concentrating the hexane solution some t-clehydroandrosterone may be recovered. The alkaline filtrate yields on acidification and extraction with ether a crystallised acid fraction which melts at 250 C., may be recrystallized from acetone and consists of A 3,t,1'7-dihydroxy-aetiocholenic acid or its 17- acetate.

The chief fraction insoluble in hexane is recrystallized from acetone or methanol and/or sublimed in a high vacuum (0.01 mm.) at 240 C., in this manner pure A -3.t.17-dihydroxy-aetiocholenic acid amide of melting point 295 to 296 C. is obtained. The same compound is obtained for instance by allowing the original reaction mixture to stand for about 8 days at 0 C. or by starting from a mixture of 17 isomeric cyanohydrin esters instead of from a pure t-dehydro-androsterone cyanohydrin diacetate. By standing over night in acetic anhydride and pyridine it yields a 3-mono-acetate which sublimes quickly already at 220 C. under 0.001 mm. pressure; when this is recrystallised from dilute acetone it melts at about 269 to 270 C.

The crude dihydroxy acid amide which is obtainable may with advantage be used directly for the saponification to the carboxylic acid described in Example 2. It appears to contain still a small proportion of A -3,t-hydroxy-l'l-acetoxyaetiocholenic acid amide. When either of the said acetates is heated for 6 hours under refluxwith a solution of 10 per cent strength of sodium hydroxide in methyl alcohol of per cent strength, it becomes, with formation of only a quite small proportion of acid, the aforesaid A -3,t,17-dihydroxy-aetiocholenic acid amide.

Example 2 1 part of t-dehydroandrosterone-cyanohydrindiacetate, 3 parts of ethylene chloride, 1.5 parts of ethyl alcohol and 1.5 parts of hydrogen chloride are together heated in a sealed tube for 3 hours at 60 C. The clear hardly colored solution is then poured into water. The ethylene chloride evaporated in the vacuum and the supernatant water decanted from the reaction product. The latter is heated for 2 hours to boiling with 50 parts of a methanol solution of 20 per cent. strength of caustic soda, the solution is poured in water and the precipitated flocks filtered, washed with normal caustic soda lye and water and dried in a vacuum. The dry substance is extracted at boiling temperature twice, each time with 50 parts of hexane, and the portion which is insoluble in hexane is recrystallized from acetone. The beautiful needles thus obtained are the A -3,t,1'7-dihydroxy-aetio-cholenic acidamide The whole is now.

already described in Example 1. 'They melt at 294 to 296 C. with decomposition.

0.5 part of this compound, together with the small acid fraction obtained by the treatment with alkali is heated with 50 parts of a 2-n-soluti'onof sodium hydroxide in n-propyl alcohol of percent strength for 5 hours in the oil bath at C. under reflux. The whole is then poured into water and the alkaline solution is extracted with ether. The ethereal solution is washed with n-caustic soda lye and the united alkaline phases are acidified and extracted with ether. This ethereal solution yields a residue from which by recrystallisation from acetone the A 3,t,l7-dihydroxy-aetio-cholenic acid is obtained in the form of quite fine strongly electrical small needles which melt withdecomposition at 267 to 268 C. This saponification may also be conducted instead.

Example 3 1 part of t-dehydroandrosterone-cyanohydrindiacetate is allowed to stand for 10 days at room temperature with 3 parts of chloroform and 3 parts of alcoholic hydrochloric acid containing 1.5 parts of hydrogen chloride; the whole is then heated under reflux for half an hour at 70 0., whereby a crystalline precipitate is produced. Water is added, the chloroform is evaporated in a vacuum and the supernatant water is decanted; from the precipitate. The latter. is heated for 2 hours under reflux with 30 parts of a methanolic solution of 30 per cent strength of caustic soda, the whole is then poured into Water and the precipitated flocks are filtered, washed with n-caustic soda lyeand water and dried. The dry matter is then extracted with a little boiling. hexane and recrystallized from acetone. and/or, sublimed at 200 C. in a high vacuum. There is thus ob.-

tained in brilliant hexagonal crystals a product I which is strongly hygroscopic and essentially more freely soluble than the acid amide derivatives hitherto described. Itmelts at 254 to 258?. C. with decomposition and has probably the constitution of a A -3,t-hydroxyeaetio-choladiene acid amide.

What we claim is: r 1. The carboxylic acid amides of the saturated and unsaturated cyclopentanopolyhydrophenan- 'threne series, containing in ut-position to the sub.-

stituted carboxyl group a memberof the group consisting of a free. and an esterified hydroxyl group. A,

2. The saturated and unsaturated aetiocholenic acide amides, containing in 3- and in I i-position a member of the group consisting ofa free and 

